1. Field
The present invention relates to a sustained drug-releasing stent useful for treatment of a constricted blood vessel, a method of making the same and a method of controlling the rate of release of the sustained release drug from the stent. More specifically, the present invention relates to a stent carrying a vascular intimal hyperplasia inhibitor, which does not inhibit proliferation of endothelial cells, a method of making such stent and a method of controlling the rate of release of the inhibitor from the stent.
2. Description of the Related Art
In recent years, the stent treatment is getting popular in the field of medical treatment, in which an affected area of the coronary artery having been constricted as a result of progress of arteriosclerosis is mechanically expanded with the aid of a balloon catheter, followed by placement of a metallic stent within the vascular lumen to restore the flow of blood. Development of the stent treatment is indeed a good news to patients suffering from arterial stenosis. However, placement of such a stent in the coronary artery, of which constriction or occlusion is highly fatal, has been found involving the probability of postoperative treatment required reaches 20 to 30% because even though the stent has been placed, vascular intimal hyperplasia occurs with the vascular lumen narrowed consequently. In view of the above, in order to decrease the in-stent restenosis, attempts have been made to design a stent of a type having its surface carrying a drug effective to exhibit restenosis prevention effects so that the drug, when the stent is placed in an artery, can be released in a controlled manner within the vascular lumen to thereby suppress the restenosis. Those attempts have led to commercialization of drug releasing stents (hereinafter referred to as DES) utilizing sirolimus (immunosuppresssor) and paclitaxel (anticancer drug). However, since those drugs have an effect of inhibiting the proliferation of vascular cells (endothelial cells and smooth muscle cells) by acting on the cell cycle thereof, not only can the vascular intimal hyperplasia resulting from an excessive proliferation of the smooth muscle cells be suppressed, but proliferation of the endothelial cells once denuded during placement of the stent is also suppressed, resulting in an adverse effect of the repair or treatment of the inner wall of a blood vessel being retarded. In view of the fact that thrombosis tends to occur easily at the site of the inner wall of a blood vessel that are not covered with endothelial cells, an antithrombotic drug must be administrated for a prolonged time, say, half a year or so and, even though the antithrombotic drug is administrated, there is a risk that the late thrombosis may result in accompanied by a sudden death.
The first event occurring in the causal sequence from the intravascular stent placement to the in-stent restenosis is said to be an “injury to the blood vessel at the time of placement of the stent, particularly an injury to the endothelial cells”, which leads to a causal consequence of “formation of blood clots”, “adhesion or infiltration of leukocytes into the blood wall”, “inflammation”, “proliferation of smooth muscle cells” and “stenosis” in this order. Accordingly, it is expected that suppression of the formation of blood clots is effective to inhibit the stenosis and, based on this view, application of an antithrombotic drug such as, for example, heparin or hirudin to form a drug releasing stent has been strenuously tried at the initial stage of development thereof, but the clinical effect tiveness thereof has not been ascertained. Now that the drug releasing stent utilizing sirolimus or paclitaxel has been widespread in these days, the drug releasing stent coated with the antithrombotic drug has been minor candidate in the development of drug releasing stents. At present, however, no drug releasing stent capable of accomplishing a sustained release of a vascular intimal hyperplasia inhibitor, which is free from injury to the endothelial cells, has yet been made available.
On the other hand, the Patent Document 1 listed below discloses in an embodiment of the invention thereof, a stent capable of releasing both of argatroban (anticoagulant agent) and cilostazol (antiplatelet agent). The Patent Document 2 also listed below discloses the rate of release of the drug from a polymer film containing argatroban, immersed in a solution of phosphate buffer (pH 7.4) for three weeks. In any event, however, no surprising effect of inhibiting the vascular intimal hyperplasia while the drug is carried by the stent has yet been observed.    [Patent Document 1] JP Laid-open Patent Publication No. 2001-190687    [Patent Document 2] WO2007/058190